TY - JOUR T1 - Genomic analyses identify hundreds of variants associated with age at menarche and support a role for puberty timing in cancer risk. JF - Nat Genet Y1 - 2017 A1 - Day, Felix R A1 - Thompson, Deborah J A1 - Helgason, Hannes A1 - Chasman, Daniel I A1 - Finucane, Hilary A1 - Sulem, Patrick A1 - Ruth, Katherine S A1 - Whalen, Sean A1 - Sarkar, Abhishek K A1 - Albrecht, Eva A1 - Altmaier, Elisabeth A1 - Amini, Marzyeh A1 - Barbieri, Caterina M A1 - Boutin, Thibaud A1 - Campbell, Archie A1 - Demerath, Ellen A1 - Giri, Ayush A1 - He, Chunyan A1 - Hottenga, Jouke J A1 - Karlsson, Robert A1 - Kolcic, Ivana A1 - Loh, Po-Ru A1 - Lunetta, Kathryn L A1 - Mangino, Massimo A1 - Marco, Brumat A1 - McMahon, George A1 - Medland, Sarah E A1 - Nolte, Ilja M A1 - Noordam, Raymond A1 - Nutile, Teresa A1 - Paternoster, Lavinia A1 - Perjakova, Natalia A1 - Porcu, Eleonora A1 - Rose, Lynda M A1 - Schraut, Katharina E A1 - Segrè, Ayellet V A1 - Smith, Albert V A1 - Stolk, Lisette A1 - Teumer, Alexander A1 - Andrulis, Irene L A1 - Bandinelli, Stefania A1 - Beckmann, Matthias W A1 - Benitez, Javier A1 - Bergmann, Sven A1 - Bochud, Murielle A1 - Boerwinkle, Eric A1 - Bojesen, Stig E A1 - Bolla, Manjeet K A1 - Brand, Judith S A1 - Brauch, Hiltrud A1 - Brenner, Hermann A1 - Broer, Linda A1 - Brüning, Thomas A1 - Buring, Julie E A1 - Campbell, Harry A1 - Catamo, Eulalia A1 - Chanock, Stephen A1 - Chenevix-Trench, Georgia A1 - Corre, Tanguy A1 - Couch, Fergus J A1 - Cousminer, Diana L A1 - Cox, Angela A1 - Crisponi, Laura A1 - Czene, Kamila A1 - Davey Smith, George A1 - de Geus, Eco J C N A1 - de Mutsert, Renée A1 - De Vivo, Immaculata A1 - Dennis, Joe A1 - Devilee, Peter A1 - Dos-Santos-Silva, Isabel A1 - Dunning, Alison M A1 - Eriksson, Johan G A1 - Fasching, Peter A A1 - Fernández-Rhodes, Lindsay A1 - Ferrucci, Luigi A1 - Flesch-Janys, Dieter A1 - Franke, Lude A1 - Gabrielson, Marike A1 - Gandin, Ilaria A1 - Giles, Graham G A1 - Grallert, Harald A1 - Gudbjartsson, Daniel F A1 - Guenel, Pascal A1 - Hall, Per A1 - Hallberg, Emily A1 - Hamann, Ute A1 - Harris, Tamara B A1 - Hartman, Catharina A A1 - Heiss, Gerardo A1 - Hooning, Maartje J A1 - Hopper, John L A1 - Hu, Frank A1 - Hunter, David J A1 - Ikram, M Arfan A1 - Im, Hae Kyung A1 - Järvelin, Marjo-Riitta A1 - Joshi, Peter K A1 - Karasik, David A1 - Kellis, Manolis A1 - Kutalik, Zoltán A1 - LaChance, Genevieve A1 - Lambrechts, Diether A1 - Langenberg, Claudia A1 - Launer, Lenore J A1 - Laven, Joop S E A1 - Lenarduzzi, Stefania A1 - Li, Jingmei A1 - Lind, Penelope A A1 - Lindström, Sara A1 - Liu, Yongmei A1 - Luan, Jian'an A1 - Mägi, Reedik A1 - Mannermaa, Arto A1 - Mbarek, Hamdi A1 - McCarthy, Mark I A1 - Meisinger, Christa A1 - Meitinger, Thomas A1 - Menni, Cristina A1 - Metspalu, Andres A1 - Michailidou, Kyriaki A1 - Milani, Lili A1 - Milne, Roger L A1 - Montgomery, Grant W A1 - Mulligan, Anna M A1 - Nalls, Mike A A1 - Navarro, Pau A1 - Nevanlinna, Heli A1 - Nyholt, Dale R A1 - Oldehinkel, Albertine J A1 - O'Mara, Tracy A A1 - Padmanabhan, Sandosh A1 - Palotie, Aarno A1 - Pedersen, Nancy A1 - Peters, Annette A1 - Peto, Julian A1 - Pharoah, Paul D P A1 - Pouta, Anneli A1 - Radice, Paolo A1 - Rahman, Iffat A1 - Ring, Susan M A1 - Robino, Antonietta A1 - Rosendaal, Frits R A1 - Rudan, Igor A1 - Rueedi, Rico A1 - Ruggiero, Daniela A1 - Sala, Cinzia F A1 - Schmidt, Marjanka K A1 - Scott, Robert A A1 - Shah, Mitul A1 - Sorice, Rossella A1 - Southey, Melissa C A1 - Sovio, Ulla A1 - Stampfer, Meir A1 - Steri, Maristella A1 - Strauch, Konstantin A1 - Tanaka, Toshiko A1 - Tikkanen, Emmi A1 - Timpson, Nicholas J A1 - Traglia, Michela A1 - Truong, Therese A1 - Tyrer, Jonathan P A1 - Uitterlinden, André G A1 - Edwards, Digna R Velez A1 - Vitart, Veronique A1 - Völker, Uwe A1 - Vollenweider, Peter A1 - Wang, Qin A1 - Widen, Elisabeth A1 - van Dijk, Ko Willems A1 - Willemsen, Gonneke A1 - Winqvist, Robert A1 - Wolffenbuttel, Bruce H R A1 - Zhao, Jing Hua A1 - Zoledziewska, Magdalena A1 - Zygmunt, Marek A1 - Alizadeh, Behrooz Z A1 - Boomsma, Dorret I A1 - Ciullo, Marina A1 - Cucca, Francesco A1 - Esko, Tõnu A1 - Franceschini, Nora A1 - Gieger, Christian A1 - Gudnason, Vilmundur A1 - Hayward, Caroline A1 - Kraft, Peter A1 - Lawlor, Debbie A A1 - Magnusson, Patrik K E A1 - Martin, Nicholas G A1 - Mook-Kanamori, Dennis O A1 - Nohr, Ellen A A1 - Polasek, Ozren A1 - Porteous, David A1 - Price, Alkes L A1 - Ridker, Paul M A1 - Snieder, Harold A1 - Spector, Tim D A1 - Stöckl, Doris A1 - Toniolo, Daniela A1 - Ulivi, Sheila A1 - Visser, Jenny A A1 - Völzke, Henry A1 - Wareham, Nicholas J A1 - Wilson, James F A1 - Spurdle, Amanda B A1 - Thorsteindottir, Unnur A1 - Pollard, Katherine S A1 - Easton, Douglas F A1 - Tung, Joyce Y A1 - Chang-Claude, Jenny A1 - Hinds, David A1 - Murray, Anna A1 - Murabito, Joanne M A1 - Stefansson, Kari A1 - Ong, Ken K A1 - Perry, John R B KW - Adolescent KW - Age Factors KW - Body Mass Index KW - Databases, Genetic KW - Female KW - Genetic Predisposition to Disease KW - Genome-Wide Association Study KW - Genomic Imprinting KW - Humans KW - Intercellular Signaling Peptides and Proteins KW - Male KW - Membrane Proteins KW - Menarche KW - Neoplasms KW - Polymorphism, Single Nucleotide KW - Puberty KW - Quantitative Trait Loci KW - Ribonucleoproteins KW - Risk Factors AB -

The timing of puberty is a highly polygenic childhood trait that is epidemiologically associated with various adult diseases. Using 1000 Genomes Project-imputed genotype data in up to ∼370,000 women, we identify 389 independent signals (P < 5 × 10) for age at menarche, a milestone in female pubertal development. In Icelandic data, these signals explain ∼7.4% of the population variance in age at menarche, corresponding to ∼25% of the estimated heritability. We implicate ∼250 genes via coding variation or associated expression, demonstrating significant enrichment in neural tissues. Rare variants near the imprinted genes MKRN3 and DLK1 were identified, exhibiting large effects when paternally inherited. Mendelian randomization analyses suggest causal inverse associations, independent of body mass index (BMI), between puberty timing and risks for breast and endometrial cancers in women and prostate cancer in men. In aggregate, our findings highlight the complexity of the genetic regulation of puberty timing and support causal links with cancer susceptibility.

VL - 49 IS - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28436984?dopt=Abstract ER - TY - JOUR T1 - Rare and low-frequency coding variants alter human adult height. JF - Nature Y1 - 2017 A1 - Marouli, Eirini A1 - Graff, Mariaelisa A1 - Medina-Gomez, Carolina A1 - Lo, Ken Sin A1 - Wood, Andrew R A1 - Kjaer, Troels R A1 - Fine, Rebecca S A1 - Lu, Yingchang A1 - Schurmann, Claudia A1 - Highland, Heather M A1 - Rüeger, Sina A1 - Thorleifsson, Gudmar A1 - Justice, Anne E A1 - Lamparter, David A1 - Stirrups, Kathleen E A1 - Turcot, Valérie A1 - Young, Kristin L A1 - Winkler, Thomas W A1 - Esko, Tõnu A1 - Karaderi, Tugce A1 - Locke, Adam E A1 - Masca, Nicholas G D A1 - Ng, Maggie C Y A1 - Mudgal, Poorva A1 - Rivas, Manuel A A1 - Vedantam, Sailaja A1 - Mahajan, Anubha A1 - Guo, Xiuqing A1 - Abecasis, Goncalo A1 - Aben, Katja K A1 - Adair, Linda S A1 - Alam, Dewan S A1 - Albrecht, Eva A1 - Allin, Kristine H A1 - Allison, Matthew A1 - Amouyel, Philippe A1 - Appel, Emil V A1 - Arveiler, Dominique A1 - Asselbergs, Folkert W A1 - Auer, Paul L A1 - Balkau, Beverley A1 - Banas, Bernhard A1 - Bang, Lia E A1 - Benn, Marianne A1 - Bergmann, Sven A1 - Bielak, Lawrence F A1 - Blüher, Matthias A1 - Boeing, Heiner A1 - Boerwinkle, Eric A1 - Böger, Carsten A A1 - Bonnycastle, Lori L A1 - Bork-Jensen, Jette A1 - Bots, Michiel L A1 - Bottinger, Erwin P A1 - Bowden, Donald W A1 - Brandslund, Ivan A1 - Breen, Gerome A1 - Brilliant, Murray H A1 - Broer, Linda A1 - Burt, Amber A A1 - Butterworth, Adam S A1 - Carey, David J A1 - Caulfield, Mark J A1 - Chambers, John C A1 - Chasman, Daniel I A1 - Chen, Yii-Der Ida A1 - Chowdhury, Rajiv A1 - Christensen, Cramer A1 - Chu, Audrey Y A1 - Cocca, Massimiliano A1 - Collins, Francis S A1 - Cook, James P A1 - Corley, Janie A1 - Galbany, Jordi Corominas A1 - Cox, Amanda J A1 - Cuellar-Partida, Gabriel A1 - Danesh, John A1 - Davies, Gail A1 - de Bakker, Paul I W A1 - de Borst, Gert J A1 - de Denus, Simon A1 - de Groot, Mark C H A1 - de Mutsert, Renée A1 - Deary, Ian J A1 - Dedoussis, George A1 - Demerath, Ellen W A1 - den Hollander, Anneke I A1 - Dennis, Joe G A1 - Di Angelantonio, Emanuele A1 - Drenos, Fotios A1 - Du, Mengmeng A1 - Dunning, Alison M A1 - Easton, Douglas F A1 - Ebeling, Tapani A1 - Edwards, Todd L A1 - Ellinor, Patrick T A1 - Elliott, Paul A1 - Evangelou, Evangelos A1 - Farmaki, Aliki-Eleni A1 - Faul, Jessica D A1 - Feitosa, Mary F A1 - Feng, Shuang A1 - Ferrannini, Ele A1 - Ferrario, Marco M A1 - Ferrières, Jean A1 - Florez, Jose C A1 - Ford, Ian A1 - Fornage, Myriam A1 - Franks, Paul W A1 - Frikke-Schmidt, Ruth A1 - Galesloot, Tessel E A1 - Gan, Wei A1 - Gandin, Ilaria A1 - Gasparini, Paolo A1 - Giedraitis, Vilmantas A1 - Giri, Ayush A1 - Girotto, Giorgia A1 - Gordon, Scott D A1 - Gordon-Larsen, Penny A1 - Gorski, Mathias A1 - Grarup, Niels A1 - Grove, Megan L A1 - Gudnason, Vilmundur A1 - Gustafsson, Stefan A1 - Hansen, Torben A1 - Harris, Kathleen Mullan A1 - Harris, Tamara B A1 - Hattersley, Andrew T A1 - Hayward, Caroline A1 - He, Liang A1 - Heid, Iris M A1 - Heikkilä, Kauko A1 - Helgeland, Øyvind A1 - Hernesniemi, Jussi A1 - Hewitt, Alex W A1 - Hocking, Lynne J A1 - Hollensted, Mette A1 - Holmen, Oddgeir L A1 - Hovingh, G Kees A1 - Howson, Joanna M M A1 - Hoyng, Carel B A1 - Huang, Paul L A1 - Hveem, Kristian A1 - Ikram, M Arfan A1 - Ingelsson, Erik A1 - Jackson, Anne U A1 - Jansson, Jan-Håkan A1 - Jarvik, Gail P A1 - Jensen, Gorm B A1 - Jhun, Min A A1 - Jia, Yucheng A1 - Jiang, Xuejuan A1 - Johansson, Stefan A1 - Jørgensen, Marit E A1 - Jørgensen, Torben A1 - Jousilahti, Pekka A1 - Jukema, J Wouter A1 - Kahali, Bratati A1 - Kahn, René S A1 - Kähönen, Mika A1 - Kamstrup, Pia R A1 - Kanoni, Stavroula A1 - Kaprio, Jaakko A1 - Karaleftheri, Maria A1 - Kardia, Sharon L R A1 - Karpe, Fredrik A1 - Kee, Frank A1 - Keeman, Renske A1 - Kiemeney, Lambertus A A1 - Kitajima, Hidetoshi A1 - Kluivers, Kirsten B A1 - Kocher, Thomas A1 - Komulainen, Pirjo A1 - Kontto, Jukka A1 - Kooner, Jaspal S A1 - Kooperberg, Charles A1 - Kovacs, Peter A1 - Kriebel, Jennifer A1 - Kuivaniemi, Helena A1 - Küry, Sébastien A1 - Kuusisto, Johanna A1 - La Bianca, Martina A1 - Laakso, Markku A1 - Lakka, Timo A A1 - Lange, Ethan M A1 - Lange, Leslie A A1 - Langefeld, Carl D A1 - Langenberg, Claudia A1 - Larson, Eric B A1 - Lee, I-Te A1 - Lehtimäki, Terho A1 - Lewis, Cora E A1 - Li, Huaixing A1 - Li, Jin A1 - Li-Gao, Ruifang A1 - Lin, Honghuang A1 - Lin, Li-An A1 - Lin, Xu A1 - Lind, Lars A1 - Lindström, Jaana A1 - Linneberg, Allan A1 - Liu, Yeheng A1 - Liu, Yongmei A1 - Lophatananon, Artitaya A1 - Luan, Jian'an A1 - Lubitz, Steven A A1 - Lyytikäinen, Leo-Pekka A1 - Mackey, David A A1 - Madden, Pamela A F A1 - Manning, Alisa K A1 - Männistö, Satu A1 - Marenne, Gaëlle A1 - Marten, Jonathan A1 - Martin, Nicholas G A1 - Mazul, Angela L A1 - Meidtner, Karina A1 - Metspalu, Andres A1 - Mitchell, Paul A1 - Mohlke, Karen L A1 - Mook-Kanamori, Dennis O A1 - Morgan, Anna A1 - Morris, Andrew D A1 - Morris, Andrew P A1 - Müller-Nurasyid, Martina A1 - Munroe, Patricia B A1 - Nalls, Mike A A1 - Nauck, Matthias A1 - Nelson, Christopher P A1 - Neville, Matt A1 - Nielsen, Sune F A1 - Nikus, Kjell A1 - Njølstad, Pål R A1 - Nordestgaard, Børge G A1 - Ntalla, Ioanna A1 - O'Connel, Jeffrey R A1 - Oksa, Heikki A1 - Loohuis, Loes M Olde A1 - Ophoff, Roel A A1 - Owen, Katharine R A1 - Packard, Chris J A1 - Padmanabhan, Sandosh A1 - Palmer, Colin N A A1 - Pasterkamp, Gerard A1 - Patel, Aniruddh P A1 - Pattie, Alison A1 - Pedersen, Oluf A1 - Peissig, Peggy L A1 - Peloso, Gina M A1 - Pennell, Craig E A1 - Perola, Markus A1 - Perry, James A A1 - Perry, John R B A1 - Person, Thomas N A1 - Pirie, Ailith A1 - Polasek, Ozren A1 - Posthuma, Danielle A1 - Raitakari, Olli T A1 - Rasheed, Asif A1 - Rauramaa, Rainer A1 - Reilly, Dermot F A1 - Reiner, Alex P A1 - Renstrom, Frida A1 - Ridker, Paul M A1 - Rioux, John D A1 - Robertson, Neil A1 - Robino, Antonietta A1 - Rolandsson, Olov A1 - Rudan, Igor A1 - Ruth, Katherine S A1 - Saleheen, Danish A1 - Salomaa, Veikko A1 - Samani, Nilesh J A1 - Sandow, Kevin A1 - Sapkota, Yadav A1 - Sattar, Naveed A1 - Schmidt, Marjanka K A1 - Schreiner, Pamela J A1 - Schulze, Matthias B A1 - Scott, Robert A A1 - Segura-Lepe, Marcelo P A1 - Shah, Svati A1 - Sim, Xueling A1 - Sivapalaratnam, Suthesh A1 - Small, Kerrin S A1 - Smith, Albert Vernon A1 - Smith, Jennifer A A1 - Southam, Lorraine A1 - Spector, Timothy D A1 - Speliotes, Elizabeth K A1 - Starr, John M A1 - Steinthorsdottir, Valgerdur A1 - Stringham, Heather M A1 - Stumvoll, Michael A1 - Surendran, Praveen A1 - 't Hart, Leen M A1 - Tansey, Katherine E A1 - Tardif, Jean-Claude A1 - Taylor, Kent D A1 - Teumer, Alexander A1 - Thompson, Deborah J A1 - Thorsteinsdottir, Unnur A1 - Thuesen, Betina H A1 - Tönjes, Anke A1 - Tromp, Gerard A1 - Trompet, Stella A1 - Tsafantakis, Emmanouil A1 - Tuomilehto, Jaakko A1 - Tybjaerg-Hansen, Anne A1 - Tyrer, Jonathan P A1 - Uher, Rudolf A1 - Uitterlinden, André G A1 - Ulivi, Sheila A1 - van der Laan, Sander W A1 - Van Der Leij, Andries R A1 - van Duijn, Cornelia M A1 - van Schoor, Natasja M A1 - van Setten, Jessica A1 - Varbo, Anette A1 - Varga, Tibor V A1 - Varma, Rohit A1 - Edwards, Digna R Velez A1 - Vermeulen, Sita H A1 - Vestergaard, Henrik A1 - Vitart, Veronique A1 - Vogt, Thomas F A1 - Vozzi, Diego A1 - Walker, Mark A1 - Wang, Feijie A1 - Wang, Carol A A1 - Wang, Shuai A1 - Wang, Yiqin A1 - Wareham, Nicholas J A1 - Warren, Helen R A1 - Wessel, Jennifer A1 - Willems, Sara M A1 - Wilson, James G A1 - Witte, Daniel R A1 - Woods, Michael O A1 - Wu, Ying A1 - Yaghootkar, Hanieh A1 - Yao, Jie A1 - Yao, Pang A1 - Yerges-Armstrong, Laura M A1 - Young, Robin A1 - Zeggini, Eleftheria A1 - Zhan, Xiaowei A1 - Zhang, Weihua A1 - Zhao, Jing Hua A1 - Zhao, Wei A1 - Zhao, Wei A1 - Zheng, He A1 - Zhou, Wei A1 - Rotter, Jerome I A1 - Boehnke, Michael A1 - Kathiresan, Sekar A1 - McCarthy, Mark I A1 - Willer, Cristen J A1 - Stefansson, Kari A1 - Borecki, Ingrid B A1 - Liu, Dajiang J A1 - North, Kari E A1 - Heard-Costa, Nancy L A1 - Pers, Tune H A1 - Lindgren, Cecilia M A1 - Oxvig, Claus A1 - Kutalik, Zoltán A1 - Rivadeneira, Fernando A1 - Loos, Ruth J F A1 - Frayling, Timothy M A1 - Hirschhorn, Joel N A1 - Deloukas, Panos A1 - Lettre, Guillaume KW - ADAMTS Proteins KW - Adult KW - Alleles KW - Body Height KW - Cell Adhesion Molecules KW - Female KW - Gene Frequency KW - Genetic Variation KW - Genome, Human KW - Glycoproteins KW - Glycosaminoglycans KW - Hedgehog Proteins KW - Humans KW - Intercellular Signaling Peptides and Proteins KW - Interferon Regulatory Factors KW - Interleukin-11 Receptor alpha Subunit KW - Male KW - Multifactorial Inheritance KW - NADPH Oxidase 4 KW - NADPH Oxidases KW - Phenotype KW - Pregnancy-Associated Plasma Protein-A KW - Procollagen N-Endopeptidase KW - Proteoglycans KW - Proteolysis KW - Receptors, Androgen KW - Somatomedins AB -

Height is a highly heritable, classic polygenic trait with approximately 700 common associated variants identified through genome-wide association studies so far. Here, we report 83 height-associated coding variants with lower minor-allele frequencies (in the range of 0.1-4.8%) and effects of up to 2 centimetres per allele (such as those in IHH, STC2, AR and CRISPLD2), greater than ten times the average effect of common variants. In functional follow-up studies, rare height-increasing alleles of STC2 (giving an increase of 1-2 centimetres per allele) compromised proteolytic inhibition of PAPP-A and increased cleavage of IGFBP-4 in vitro, resulting in higher bioavailability of insulin-like growth factors. These 83 height-associated variants overlap genes that are mutated in monogenic growth disorders and highlight new biological candidates (such as ADAMTS3, IL11RA and NOX4) and pathways (such as proteoglycan and glycosaminoglycan synthesis) involved in growth. Our results demonstrate that sufficiently large sample sizes can uncover rare and low-frequency variants of moderate-to-large effect associated with polygenic human phenotypes, and that these variants implicate relevant genes and pathways.

VL - 542 IS - 7640 U1 - http://www.ncbi.nlm.nih.gov/pubmed/28146470?dopt=Abstract ER - TY - JOUR T1 - Large-scale genomic analyses link reproductive aging to hypothalamic signaling, breast cancer susceptibility and BRCA1-mediated DNA repair. JF - Nat Genet Y1 - 2015 A1 - Day, Felix R A1 - Ruth, Katherine S A1 - Thompson, Deborah J A1 - Lunetta, Kathryn L A1 - Pervjakova, Natalia A1 - Chasman, Daniel I A1 - Stolk, Lisette A1 - Finucane, Hilary K A1 - Sulem, Patrick A1 - Bulik-Sullivan, Brendan A1 - Esko, Tõnu A1 - Johnson, Andrew D A1 - Elks, Cathy E A1 - Franceschini, Nora A1 - He, Chunyan A1 - Altmaier, Elisabeth A1 - Brody, Jennifer A A1 - Franke, Lude L A1 - Huffman, Jennifer E A1 - Keller, Margaux F A1 - McArdle, Patrick F A1 - Nutile, Teresa A1 - Porcu, Eleonora A1 - Robino, Antonietta A1 - Rose, Lynda M A1 - Schick, Ursula M A1 - Smith, Jennifer A A1 - Teumer, Alexander A1 - Traglia, Michela A1 - Vuckovic, Dragana A1 - Yao, Jie A1 - Zhao, Wei A1 - Albrecht, Eva A1 - Amin, Najaf A1 - Corre, Tanguy A1 - Hottenga, Jouke-Jan A1 - Mangino, Massimo A1 - Smith, Albert V A1 - Tanaka, Toshiko A1 - Abecasis, Goncalo R A1 - Andrulis, Irene L A1 - Anton-Culver, Hoda A1 - Antoniou, Antonis C A1 - Arndt, Volker A1 - Arnold, Alice M A1 - Barbieri, Caterina A1 - Beckmann, Matthias W A1 - Beeghly-Fadiel, Alicia A1 - Benitez, Javier A1 - Bernstein, Leslie A1 - Bielinski, Suzette J A1 - Blomqvist, Carl A1 - Boerwinkle, Eric A1 - Bogdanova, Natalia V A1 - Bojesen, Stig E A1 - Bolla, Manjeet K A1 - Borresen-Dale, Anne-Lise A1 - Boutin, Thibaud S A1 - Brauch, Hiltrud A1 - Brenner, Hermann A1 - Brüning, Thomas A1 - Burwinkel, Barbara A1 - Campbell, Archie A1 - Campbell, Harry A1 - Chanock, Stephen J A1 - Chapman, J Ross A1 - Chen, Yii-Der Ida A1 - Chenevix-Trench, Georgia A1 - Couch, Fergus J A1 - Coviello, Andrea D A1 - Cox, Angela A1 - Czene, Kamila A1 - Darabi, Hatef A1 - De Vivo, Immaculata A1 - Demerath, Ellen W A1 - Dennis, Joe A1 - Devilee, Peter A1 - Dörk, Thilo A1 - Dos-Santos-Silva, Isabel A1 - Dunning, Alison M A1 - Eicher, John D A1 - Fasching, Peter A A1 - Faul, Jessica D A1 - Figueroa, Jonine A1 - Flesch-Janys, Dieter A1 - Gandin, Ilaria A1 - Garcia, Melissa E A1 - García-Closas, Montserrat A1 - Giles, Graham G A1 - Girotto, Giorgia G A1 - Goldberg, Mark S A1 - González-Neira, Anna A1 - Goodarzi, Mark O A1 - Grove, Megan L A1 - Gudbjartsson, Daniel F A1 - Guenel, Pascal A1 - Guo, Xiuqing A1 - Haiman, Christopher A A1 - Hall, Per A1 - Hamann, Ute A1 - Henderson, Brian E A1 - Hocking, Lynne J A1 - Hofman, Albert A1 - Homuth, Georg A1 - Hooning, Maartje J A1 - Hopper, John L A1 - Hu, Frank B A1 - Huang, Jinyan A1 - Humphreys, Keith A1 - Hunter, David J A1 - Jakubowska, Anna A1 - Jones, Samuel E A1 - Kabisch, Maria A1 - Karasik, David A1 - Knight, Julia A A1 - Kolcic, Ivana A1 - Kooperberg, Charles A1 - Kosma, Veli-Matti A1 - Kriebel, Jennifer A1 - Kristensen, Vessela A1 - Lambrechts, Diether A1 - Langenberg, Claudia A1 - Li, Jingmei A1 - Li, Xin A1 - Lindström, Sara A1 - Liu, Yongmei A1 - Luan, Jian'an A1 - Lubinski, Jan A1 - Mägi, Reedik A1 - Mannermaa, Arto A1 - Manz, Judith A1 - Margolin, Sara A1 - Marten, Jonathan A1 - Martin, Nicholas G A1 - Masciullo, Corrado A1 - Meindl, Alfons A1 - Michailidou, Kyriaki A1 - Mihailov, Evelin A1 - Milani, Lili A1 - Milne, Roger L A1 - Müller-Nurasyid, Martina A1 - Nalls, Michael A1 - Neale, Benjamin M A1 - Nevanlinna, Heli A1 - Neven, Patrick A1 - Newman, Anne B A1 - Nordestgaard, Børge G A1 - Olson, Janet E A1 - Padmanabhan, Sandosh A1 - Peterlongo, Paolo A1 - Peters, Ulrike A1 - Petersmann, Astrid A1 - Peto, Julian A1 - Pharoah, Paul D P A1 - Pirastu, Nicola N A1 - Pirie, Ailith A1 - Pistis, Giorgio A1 - Polasek, Ozren A1 - Porteous, David A1 - Psaty, Bruce M A1 - Pylkäs, Katri A1 - Radice, Paolo A1 - Raffel, Leslie J A1 - Rivadeneira, Fernando A1 - Rudan, Igor A1 - Rudolph, Anja A1 - Ruggiero, Daniela A1 - Sala, Cinzia F A1 - Sanna, Serena A1 - Sawyer, Elinor J A1 - Schlessinger, David A1 - Schmidt, Marjanka K A1 - Schmidt, Frank A1 - Schmutzler, Rita K A1 - Schoemaker, Minouk J A1 - Scott, Robert A A1 - Seynaeve, Caroline M A1 - Simard, Jacques A1 - Sorice, Rossella A1 - Southey, Melissa C A1 - Stöckl, Doris A1 - Strauch, Konstantin A1 - Swerdlow, Anthony A1 - Taylor, Kent D A1 - Thorsteinsdottir, Unnur A1 - Toland, Amanda E A1 - Tomlinson, Ian A1 - Truong, Therese A1 - Tryggvadottir, Laufey A1 - Turner, Stephen T A1 - Vozzi, Diego A1 - Wang, Qin A1 - Wellons, Melissa A1 - Willemsen, Gonneke A1 - Wilson, James F A1 - Winqvist, Robert A1 - Wolffenbuttel, Bruce B H R A1 - Wright, Alan F A1 - Yannoukakos, Drakoulis A1 - Zemunik, Tatijana A1 - Zheng, Wei A1 - Zygmunt, Marek A1 - Bergmann, Sven A1 - Boomsma, Dorret I A1 - Buring, Julie E A1 - Ferrucci, Luigi A1 - Montgomery, Grant W A1 - Gudnason, Vilmundur A1 - Spector, Tim D A1 - van Duijn, Cornelia M A1 - Alizadeh, Behrooz Z A1 - Ciullo, Marina A1 - Crisponi, Laura A1 - Easton, Douglas F A1 - Gasparini, Paolo P A1 - Gieger, Christian A1 - Harris, Tamara B A1 - Hayward, Caroline A1 - Kardia, Sharon L R A1 - Kraft, Peter A1 - McKnight, Barbara A1 - Metspalu, Andres A1 - Morrison, Alanna C A1 - Reiner, Alex P A1 - Ridker, Paul M A1 - Rotter, Jerome I A1 - Toniolo, Daniela A1 - Uitterlinden, André G A1 - Ulivi, Sheila A1 - Völzke, Henry A1 - Wareham, Nicholas J A1 - Weir, David R A1 - Yerges-Armstrong, Laura M A1 - Price, Alkes L A1 - Stefansson, Kari A1 - Visser, Jenny A A1 - Ong, Ken K A1 - Chang-Claude, Jenny A1 - Murabito, Joanne M A1 - Perry, John R B A1 - Murray, Anna AB -

Menopause timing has a substantial impact on infertility and risk of disease, including breast cancer, but the underlying mechanisms are poorly understood. We report a dual strategy in ∼70,000 women to identify common and low-frequency protein-coding variation associated with age at natural menopause (ANM). We identified 44 regions with common variants, including two regions harboring additional rare missense alleles of large effect. We found enrichment of signals in or near genes involved in delayed puberty, highlighting the first molecular links between the onset and end of reproductive lifespan. Pathway analyses identified major association with DNA damage response (DDR) genes, including the first common coding variant in BRCA1 associated with any complex trait. Mendelian randomization analyses supported a causal effect of later ANM on breast cancer risk (∼6% increase in risk per year; P = 3 × 10(-14)), likely mediated by prolonged sex hormone exposure rather than DDR mechanisms.

VL - 47 IS - 11 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26414677?dopt=Abstract ER - TY - JOUR T1 - Rare coding variants and X-linked loci associated with age at menarche. JF - Nat Commun Y1 - 2015 A1 - Lunetta, Kathryn L A1 - Day, Felix R A1 - Sulem, Patrick A1 - Ruth, Katherine S A1 - Tung, Joyce Y A1 - Hinds, David A A1 - Esko, Tõnu A1 - Elks, Cathy E A1 - Altmaier, Elisabeth A1 - He, Chunyan A1 - Huffman, Jennifer E A1 - Mihailov, Evelin A1 - Porcu, Eleonora A1 - Robino, Antonietta A1 - Rose, Lynda M A1 - Schick, Ursula M A1 - Stolk, Lisette A1 - Teumer, Alexander A1 - Thompson, Deborah J A1 - Traglia, Michela A1 - Wang, Carol A A1 - Yerges-Armstrong, Laura M A1 - Antoniou, Antonis C A1 - Barbieri, Caterina A1 - Coviello, Andrea D A1 - Cucca, Francesco A1 - Demerath, Ellen W A1 - Dunning, Alison M A1 - Gandin, Ilaria A1 - Grove, Megan L A1 - Gudbjartsson, Daniel F A1 - Hocking, Lynne J A1 - Hofman, Albert A1 - Huang, Jinyan A1 - Jackson, Rebecca D A1 - Karasik, David A1 - Kriebel, Jennifer A1 - Lange, Ethan M A1 - Lange, Leslie A A1 - Langenberg, Claudia A1 - Li, Xin A1 - Luan, Jian'an A1 - Mägi, Reedik A1 - Morrison, Alanna C A1 - Padmanabhan, Sandosh A1 - Pirie, Ailith A1 - Polasek, Ozren A1 - Porteous, David A1 - Reiner, Alex P A1 - Rivadeneira, Fernando A1 - Rudan, Igor A1 - Sala, Cinzia F A1 - Schlessinger, David A1 - Scott, Robert A A1 - Stöckl, Doris A1 - Visser, Jenny A A1 - Völker, Uwe A1 - Vozzi, Diego A1 - Wilson, James G A1 - Zygmunt, Marek A1 - Boerwinkle, Eric A1 - Buring, Julie E A1 - Crisponi, Laura A1 - Easton, Douglas F A1 - Hayward, Caroline A1 - Hu, Frank B A1 - Liu, Simin A1 - Metspalu, Andres A1 - Pennell, Craig E A1 - Ridker, Paul M A1 - Strauch, Konstantin A1 - Streeten, Elizabeth A A1 - Toniolo, Daniela A1 - Uitterlinden, André G A1 - Ulivi, Sheila A1 - Völzke, Henry A1 - Wareham, Nicholas J A1 - Wellons, Melissa A1 - Franceschini, Nora A1 - Chasman, Daniel I A1 - Thorsteinsdottir, Unnur A1 - Murray, Anna A1 - Stefansson, Kari A1 - Murabito, Joanne M A1 - Ong, Ken K A1 - Perry, John R B AB -

More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only ∼3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency protein-coding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6%; effect sizes 0.08-1.25 years per allele; P<5 × 10(-8)). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P=9.4 × 10(-13)) and FAAH2 (rs5914101, P=4.9 × 10(-10)). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P=2.8 × 10(-11)), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain ∼0.5% variance, indicating that these overlooked sources of variation do not substantially explain the 'missing heritability' of this complex trait.

VL - 6 U1 - http://www.ncbi.nlm.nih.gov/pubmed/26239645?dopt=Abstract ER - TY - JOUR T1 - Parent-of-origin-specific allelic associations among 106 genomic loci for age at menarche. JF - Nature Y1 - 2014 A1 - Perry, John R B A1 - Day, Felix A1 - Elks, Cathy E A1 - Sulem, Patrick A1 - Thompson, Deborah J A1 - Ferreira, Teresa A1 - He, Chunyan A1 - Chasman, Daniel I A1 - Esko, Tõnu A1 - Thorleifsson, Gudmar A1 - Albrecht, Eva A1 - Ang, Wei Q A1 - Corre, Tanguy A1 - Cousminer, Diana L A1 - Feenstra, Bjarke A1 - Franceschini, Nora A1 - Ganna, Andrea A1 - Johnson, Andrew D A1 - Kjellqvist, Sanela A1 - Lunetta, Kathryn L A1 - McMahon, George A1 - Nolte, Ilja M A1 - Paternoster, Lavinia A1 - Porcu, Eleonora A1 - Smith, Albert V A1 - Stolk, Lisette A1 - Teumer, Alexander A1 - Tšernikova, Natalia A1 - Tikkanen, Emmi A1 - Ulivi, Sheila A1 - Wagner, Erin K A1 - Amin, Najaf A1 - Bierut, Laura J A1 - Byrne, Enda M A1 - Hottenga, Jouke-Jan A1 - Koller, Daniel L A1 - Mangino, Massimo A1 - Pers, Tune H A1 - Yerges-Armstrong, Laura M A1 - Hua Zhao, Jing A1 - Andrulis, Irene L A1 - Anton-Culver, Hoda A1 - Atsma, Femke A1 - Bandinelli, Stefania A1 - Beckmann, Matthias W A1 - Benitez, Javier A1 - Blomqvist, Carl A1 - Bojesen, Stig E A1 - Bolla, Manjeet K A1 - Bonanni, Bernardo A1 - Brauch, Hiltrud A1 - Brenner, Hermann A1 - Buring, Julie E A1 - Chang-Claude, Jenny A1 - Chanock, Stephen A1 - Chen, Jinhui A1 - Chenevix-Trench, Georgia A1 - Collée, J Margriet A1 - Couch, Fergus J A1 - Couper, David A1 - Coviello, Andrea D A1 - Cox, Angela A1 - Czene, Kamila A1 - d'Adamo, Adamo Pio A1 - Davey Smith, George A1 - De Vivo, Immaculata A1 - Demerath, Ellen W A1 - Dennis, Joe A1 - Devilee, Peter A1 - Dieffenbach, Aida K A1 - Dunning, Alison M A1 - Eiriksdottir, Gudny A1 - Eriksson, Johan G A1 - Fasching, Peter A A1 - Ferrucci, Luigi A1 - Flesch-Janys, Dieter A1 - Flyger, Henrik A1 - Foroud, Tatiana A1 - Franke, Lude A1 - Garcia, Melissa E A1 - García-Closas, Montserrat A1 - Geller, Frank A1 - de Geus, Eco E J A1 - Giles, Graham G A1 - Gudbjartsson, Daniel F A1 - Gudnason, Vilmundur A1 - Guenel, Pascal A1 - Guo, Suiqun A1 - Hall, Per A1 - Hamann, Ute A1 - Haring, Robin A1 - Hartman, Catharina A A1 - Heath, Andrew C A1 - Hofman, Albert A1 - Hooning, Maartje J A1 - Hopper, John L A1 - Hu, Frank B A1 - Hunter, David J A1 - Karasik, David A1 - Kiel, Douglas P A1 - Knight, Julia A A1 - Kosma, Veli-Matti A1 - Kutalik, Zoltán A1 - Lai, Sandra A1 - Lambrechts, Diether A1 - Lindblom, Annika A1 - Mägi, Reedik A1 - Magnusson, Patrik K A1 - Mannermaa, Arto A1 - Martin, Nicholas G A1 - Masson, Gisli A1 - McArdle, Patrick F A1 - McArdle, Wendy L A1 - Melbye, Mads A1 - Michailidou, Kyriaki A1 - Mihailov, Evelin A1 - Milani, Lili A1 - Milne, Roger L A1 - Nevanlinna, Heli A1 - Neven, Patrick A1 - Nohr, Ellen A A1 - Oldehinkel, Albertine J A1 - Oostra, Ben A A1 - Palotie, Aarno A1 - Peacock, Munro A1 - Pedersen, Nancy L A1 - Peterlongo, Paolo A1 - Peto, Julian A1 - Pharoah, Paul D P A1 - Postma, Dirkje S A1 - Pouta, Anneli A1 - Pylkäs, Katri A1 - Radice, Paolo A1 - Ring, Susan A1 - Rivadeneira, Fernando A1 - Robino, Antonietta A1 - Rose, Lynda M A1 - Rudolph, Anja A1 - Salomaa, Veikko A1 - Sanna, Serena A1 - Schlessinger, David A1 - Schmidt, Marjanka K A1 - Southey, Mellissa C A1 - Sovio, Ulla A1 - Stampfer, Meir J A1 - Stöckl, Doris A1 - Storniolo, Anna M A1 - Timpson, Nicholas J A1 - Tyrer, Jonathan A1 - Visser, Jenny A A1 - Vollenweider, Peter A1 - Völzke, Henry A1 - Waeber, Gerard A1 - Waldenberger, Melanie A1 - Wallaschofski, Henri A1 - Wang, Qin A1 - Willemsen, Gonneke A1 - Winqvist, Robert A1 - Wolffenbuttel, Bruce H R A1 - Wright, Margaret J A1 - Boomsma, Dorret I A1 - Econs, Michael J A1 - Khaw, Kay-Tee A1 - Loos, Ruth J F A1 - McCarthy, Mark I A1 - Montgomery, Grant W A1 - Rice, John P A1 - Streeten, Elizabeth A A1 - Thorsteinsdottir, Unnur A1 - van Duijn, Cornelia M A1 - Alizadeh, Behrooz Z A1 - Bergmann, Sven A1 - Boerwinkle, Eric A1 - Boyd, Heather A A1 - Crisponi, Laura A1 - Gasparini, Paolo A1 - Gieger, Christian A1 - Harris, Tamara B A1 - Ingelsson, Erik A1 - Järvelin, Marjo-Riitta A1 - Kraft, Peter A1 - Lawlor, Debbie A1 - Metspalu, Andres A1 - Pennell, Craig E A1 - Ridker, Paul M A1 - Snieder, Harold A1 - Sørensen, Thorkild I A A1 - Spector, Tim D A1 - Strachan, David P A1 - Uitterlinden, André G A1 - Wareham, Nicholas J A1 - Widen, Elisabeth A1 - Zygmunt, Marek A1 - Murray, Anna A1 - Easton, Douglas F A1 - Stefansson, Kari A1 - Murabito, Joanne M A1 - Ong, Ken K KW - Adolescent KW - Age Factors KW - Alleles KW - Body Mass Index KW - Breast Neoplasms KW - Cardiovascular Diseases KW - Child KW - Diabetes Mellitus, Type 2 KW - Europe KW - Female KW - Genetic Loci KW - Genome-Wide Association Study KW - Genomic Imprinting KW - Humans KW - Hypothalamo-Hypophyseal System KW - Intercellular Signaling Peptides and Proteins KW - Male KW - Membrane Proteins KW - Menarche KW - Obesity KW - Ovary KW - Parents KW - Polymorphism, Single Nucleotide KW - Potassium Channels, Tandem Pore Domain KW - Proteins KW - Quantitative Trait Loci KW - Receptors, GABA-B KW - Receptors, Retinoic Acid KW - Ribonucleoproteins AB -

Age at menarche is a marker of timing of puberty in females. It varies widely between individuals, is a heritable trait and is associated with risks for obesity, type 2 diabetes, cardiovascular disease, breast cancer and all-cause mortality. Studies of rare human disorders of puberty and animal models point to a complex hypothalamic-pituitary-hormonal regulation, but the mechanisms that determine pubertal timing and underlie its links to disease risk remain unclear. Here, using genome-wide and custom-genotyping arrays in up to 182,416 women of European descent from 57 studies, we found robust evidence (P < 5 × 10(-8)) for 123 signals at 106 genomic loci associated with age at menarche. Many loci were associated with other pubertal traits in both sexes, and there was substantial overlap with genes implicated in body mass index and various diseases, including rare disorders of puberty. Menarche signals were enriched in imprinted regions, with three loci (DLK1-WDR25, MKRN3-MAGEL2 and KCNK9) demonstrating parent-of-origin-specific associations concordant with known parental expression patterns. Pathway analyses implicated nuclear hormone receptors, particularly retinoic acid and γ-aminobutyric acid-B2 receptor signalling, among novel mechanisms that regulate pubertal timing in humans. Our findings suggest a genetic architecture involving at least hundreds of common variants in the coordinated timing of the pubertal transition.

VL - 514 IS - 7520 U1 - http://www.ncbi.nlm.nih.gov/pubmed/25231870?dopt=Abstract ER -